DESCRIPTION: (Applicant's Abstract) The central nervous system effects of cocaine are mediated through the direct actions of this drug on multiple neurotransmitter systems. The relevance of serotonin systems to cocaine abuse is indicated by the potent serotonin reuptake blocking properties of cocaine and by the inhibitory effects of serotonin on the rewarding and activating properties of this drug. Therefore, allelic variants and mutations of serotonin receptor genes may produce heritable alterations in cocaine responsiveness. On the basis of its anatomical distribution and pharmacology, the serotonin 5-HT2c receptor has been implicated in the serotonergic inhibition of the neural circuits that underlie the activating and reinforcing effects of cocaine. Our preliminary studies with a mutant mouse strain lacking this receptor subtype suggest that the mutants may have increased sensitivity to behavioral and electrophysiological actions of cocaine. In Aim 1, we propose to combine genetic and pharmacological approaches to examine the effects of 5-HT2c receptor stimulation on mesolimbic dopamine system activity, and on behaviors associated with that system. To better interpret phenotypic abnormalities, we will determine the extent to which the 5-HT2c receptor mutation produces baseline alterations of monoamine systems. In Aim 2, we will determine whether the absence of 5-HT2c receptors alters the sensitivity of mesolimbic DA system structures to cocaine-induced activation. Finally, we will test the hypothesis that cocaine-induced locomotion and self-administration will be enhanced in 5-HT2c receptor mutant mice. These studies will provide insights into the serotonergic mechanisms of cocaine action and into the mechanism through which a genetic alteration of serotonin system function leads to a heritable alteration in cocaine responsiveness.